3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

Abstract

The selective synthesis of fluorinated organic molecules continues to be of major importance for the development of bioactive compounds (agrochemicals and pharmaceuticals) as well as unique materials. Among the established synthetic toolbox for incorporation of fluorine-containing units, efficient and general reagents for introducing -CF2- groups have been largely neglected. Here, we present the synthesis of 3,3-difluoropropen-1-yl ammonium salts (DFPAs) as stable, and scalable gem-difluoromethylation reagents, which allow for the direct reaction with a wide range of fascinating nucleophiles. DFPAs smoothly react with N-, O-, S-, Se-, and C-nucleophiles under mild conditions without necessity of metal catalysts with exclusive regioselectivity. In this way, the presented reagents also permit the straightforward preparation of many analogues of existing pharmaceuticals.

3,3‐Difluoroallyl Sulfonium Salts: Practical and Bench‐Stable Reagents for Highly Regioselective gem‐Difluoroallylations

“…Notably, gem ‐difluoroallyl ammonium salt 1 a′ showed no activity towards aryl zinc reagent 4 a (Scheme 2c). Although 1 a′ has been used as a suitable reagent for S N 2′ reaction with heteroatomic nucleophiles, [14b] the current result demonstrates that DFAS 1 a is more reactive than its corresponding ammonium salts. The cross‐coupling of alkyl zinc reagent 4 b with 1 a has also been examined (Scheme 2d).…”

“…Very recently, two new types of gem ‐difluoroallylating reagents have been reported, namely, 3,3‐difluoroallyl ammonium salts (DFAAs) [14] and gem ‐difluoroallylborons [15] . Nevertheless, these two types of reagents are limited to the palladium‐catalyzed formation of Ar−CF 2 R bonds [14a, 15] or the metal‐free construction of RCF 2 −X (X=O, N, S, Se) bonds [14b] (Scheme 1c). To date, the efficient construction of C(sp 3 )−CF 2 R bonds with high selectivity and generality remains challenging, [16] and no example of catalytic gem ‐difluoroallylation of aliphatic substrates has been reported yet.…”

Hantzsch Ester-Mediated Visible-Light-Induced Radical Ethoxycarbonyldifluoromethylation of Aryl Alkynes: Kinetic-Controlled Stereoselective Synthesis of Z-gem-Difluoroallyl Esters

“…13 However, pharmaceuticals with gem-difluoroallylic moieties, such as Glecaprevir, Tafluprost, and so forth, 14−21 accounted for a very low proportion in known fluorine-containing pharmaceuticals, which was related to the lack of efficient synthetic approaches for such construction. 22,23 Several recent studies have focused on the synthesis of functionalized Z-allylic building blocks with gem-difluoromethylene motifs, which will undoubtedly speed up and facilitate the construction of pharmaceutically interesting molecules and advanced materials. 23−27 However, the methods to access these specific skeletons are mainly finite to the semihydrogenation and diverse cross-coupling of relatives with organometallics under certain conditions (Scheme 1a).…”

“…Meanwhile, the proportion of fluorine-containing pharmaceuticals in commercial pharmaceuticals has exceeded 20% . However, pharmaceuticals with gem -difluoroallylic moieties, such as Glecaprevir, Tafluprost, and so forth, − accounted for a very low proportion in known fluorine-containing pharmaceuticals, which was related to the lack of efficient synthetic approaches for such construction. , Several recent studies have focused on the synthesis of functionalized Z -allylic building blocks with gem -difluoromethylene motifs, which will undoubtedly speed up and facilitate the construction of pharmaceutically interesting molecules and advanced materials. − However, the methods to access these specific skeletons are mainly finite to the semihydrogenation and diverse cross-coupling of relatives with organometallics under certain conditions (Scheme a) . Inherently, all of these strategies rely on kinetic controls and the use of specific reagents. − On the other hand, photoredox catalysis with various photosensitizers has played an important role and been recognized as an efficient green process and stimulated numerous contributions of advances for the C–C bond coupling in organic synthesis in the past 2 decades. − Nevertheless, not many successful cases of the photo-induced electron transfer (PET) process for the construction of organofluorine molecules have been reported yet (Scheme b,c). , …”

Ruthenium-Catalyzed Ligand-Enabled Regiodivergent Difluoroallylation of Aryl C–H Bonds

“…9,10 A variety of bioactive molecules with a difluoroallyl group have been developed with the potential for clinical treatment, for example, tafluprost for treatment of ocular hypertension, 11 KAG-308 for treatment of colitis, 12 and glecaprevir for anti-HCV (Figure 1a). 13 Although several elegant difluoroallylating agents were successfully developed by the Beller, 14 Feng, 15 Zhang, 16 and Hartwig 9 groups, practical methods for regioselective α,αand γ,γ-difluoroallylation are significantly less studied. In 2014, the Zhang group reported a palladiumcatalyzed α,α-difluoroallylation of arylboronates with 3-bromo-3,3-difluoropropene (BDFP) under cross-coupling conditions.…”